Leonard Jason has done it again. He has applied the scientific method and come up with something that makes sense.

The IOM has, according to Jason, devised an unworkable case definition. This failure is due to lack of scientific method (coming up with a hypothesis, testing it against evidence, revising the hypothesis, and testing it again to see if it describes all known data and has predictive value).

HHS has a poor track record when it comes to epidemics of new illnesses. They not only came up with an unworkable case definition (and a ridiculous name) for ME a couple of decades ago, they ignored AIDS, are currently ignoring Lyme disease, and have consistently put the interests of the medical/industrial complex ahead of anything that resembles public health.

SEID and the definition that accompanies it are merely one more drop in the ocean of bureaucratic collusion that typifies HHS.

It takes people like Leonard Jason and his colleagues to demonstrate just how negligent HHS has been.

"Empirical methods," he says, "could have been employed to test the proposed classification system, and the committee members might have benefited from testing out their proposed model with an actual data set." This is a gentle way of saying, "you pulled this definition out of your left ear, and it doesn't work."

Here are all the ways it doesn't work, according to the report below:

1) In the first study (60 people) the definition for SEID captured 100% of the people with ME/CFS, but it also captured 33% of patients with MS, and a staggering 47% of patients with lupus.

2) In the second study (45 people), SEID captured 27% of patients with major depression.

3) In the third study (213 people), 75% of the patients who met the Fukuda criteria also met the criteria for SEID. But 44% of those who did not meet the Fukuda criteria were also diagnosed with SEID, and 47% of the patients who had fatigue from other causes - drug and alcohol related causes, psychiatric illnesses, anorexia, chronic diseases - also met the definition for SEID.

4) Using those statistics, and comparing them to the prevalence rate established by the Fukuda definition, Jason's team came up with a prevalence rate that was 2.8 times higher than the current rate. That means if the CDC says there are a million people with ME/CFS in the US, that estimate would now be 2.8 million. And the overwhelming majority of those patients would have other diseases.

Aside from the inability of the new definition to accurately identify a distinct patient population, Jason points out that this definition will ultimately make treatment research impossible: "If individuals with primary affective disorder are misdiagnosed with SEID and provided cognitive behavioral treatment, they will more likely have positive outcomes, and this may create more difficulties in understanding the effects of these interventions for those who have ME."

Jason has called for an "open and inclusive process where all parties, including key gatekeepers, including the patients, scientists, clinicians and government officials, are involved in the decision making process." However, given the abysmal lack of faith shown by HHS, it might be best to leave that department out of any substantive decision making process that involves sick people.

The Institute of Medicine recently proposed a new case definition for chronic fatigue syndrome (CFS), as well as a new name, Systemic Exertion Intolerance Disease (SEID). Contrary to the Fukuda et al.’s CFS case definition, there are few exclusionary illnesses specified for this new SEID case definition. The current study explored this decision regarding exclusionary illnesses using the SEID criteria with four distinct data sets involving patients who had been identified as having CFS, as well as healthy controls, community controls, and other illness groups. The findings indicate that many individuals from major depressive disorder illness groups as well as other medical illnesses were categorized as having SEID. The past CFS Fukuda et al. prevalence rate in a community based sample of 0.42 increased by 2.8 times with the new SEID criteria. The consequences for this broadening of the case definition are discussed.

The Institute of Medicine (IOM) [1] recently proposed a new case definition, which was intended to replace the Fukuda et al. [2] chronic fatigue syndrome (CFS) criteria, the most widely used case definition for the past twenty years. The Fukuda et al. criteria [2] require four symptoms out of a possible eight, but it is possible that some individuals who meet these diagnostic criteria do not have core symptoms of the illness, such as post-exertional malaise. With the Fukuda et al. case definition [2], there are about a million people estimated to have this illness in the US [3]. In reaction to limitations in the Fukuda et al. case definition [2], the Canadian Clinical Criteria Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) [4] was developed, and it specified core symptoms, including post-exertional malaise, impairment of memory and concentration, unrefreshing sleep, arthralgia and/or myalgia; and several autonomic, neuroendocrine, and immune manifestations. Still later, the International Consensus Criteria for Myalgic Encephalomyelitis (ME-ICC) criteria [5] were developed, and these criteria specified eight symptoms within four domains: Post-Exertional Neuroimmune Exhaustion; Neurological Impairments; Immune, Gastro-intestinal, and Genitourinary Impairments; and Energy Production/Transportation Impairments. Others have tried to develop more empiric-based methods [6]. Each of these case definitions excluded a variety of medical or psychiatric illnesses that might be the cause of the symptoms.

Recently, the IOM [1] issued a report that proposed a new name (Systemic Exertion Intolerance Disease, SEID) and case definition that included the following four symptoms: substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social or personal activities; post-exertional malaise; unrefreshing sleep; and at least one of the two following symptoms: cognitive impairment or orthostatic intolerance. Whereas the Fukuda et al. [2] CFS criteria, the ME/CFS Canadian criteria [4], and the ME-ICC criteria [5] excluded other medical and psychiatric conditions that might have produced the fatigue, the new SEID criteria [1] had a different position regarding exclusionary conditions. The IOM [1] (p. 186) document defining SEID stated: “Over the years, case definitions of ME/CFS have differed significantly in their classification of exclusionary conditions and comorbidities. As a result, a number of disorders, such as morbid obesity and an array of psychiatric disorders, are listed as exclusionary in one definition and as comorbid in another, despite the lack of scientific evidence that being affected by such disorders precludes having ME/CFS. Indeed, it has become increasingly clear that many patients with ME/CFS have other disorders as well…Some of these other disorders may develop as part of the spectrum of ME/CFS or in response to the burdens of this disorder.” In addition, within the IOM [1] (p. 185) SEID document, it states that a detailed history and comprehensive physical examination should be used “to determine a differential diagnosis and, where clinically indicated, to exclude other disorders that could cause the patient’s symptoms, as well as to identify any comorbid conditions”. More details on exclusions are provided within the IOM’s SEID Report Guide for Clinicians [7] (p. 4), where it states: “The presence of other illnesses should not preclude patients from receiving a diagnosis of ME/CFS (SEID) except in the unlikely event that all symptoms can be accounted for by these other illnesses.” The word “unlikely” conveys the impression that most other illnesses would be considered comorbid and not exclusionary as they probably would not account for the unique SEID symptoms.

The problem for diagnosticians in interpreting these guidelines is that the core IOM symptoms are not unique to SEID, as other illnesses have comparable symptoms (e.g., cancer, Hashimoto’s, lupus, chronic heart failure, multiple sclerosis, etc.). Thus, according to the above IOM guidelines, if these illnesses account for the SEID symptoms, then it is another illness and not SEID. Therefore, many illnesses are now considered a comorbid condition with SEID. However, trying to determine whether an illness is exclusionary vs. comorbid is a challenging diagnostic task. The IOM [1] (p. 187) provides the following example that illustrates this complexity: “The committee recognizes that diagnosis and treatment of comorbid conditions is necessary when caring for patients. For example, a patient with ME/CFS with a prominent history of snoring and sleep apnea may have polysomnography diagnostic of sleep apnea. Treatment with continuous positive airway pressure could improve the patient’s overall condition but not resolve all the symptoms of ME/CFS, signifying that in this individual, obstructive sleep apnea is a comorbid condition rather than the cause of the patient’s ME/CFS symptoms.” This suggests that if treatment resolved all the SEID symptoms, then the patient had another illness (in the case above, obstructive sleep apnea); however, if the treatment does not resolve the issues, than the condition is comorbid with SEID. In other words, the ability to determine if an illness is exclusionary rests on its successful treatment, and clearly, many chronic illnesses do not have treatments that cure or alleviate all symptoms.

In addition, Ze-dog [8] pointed out that this new SEID definition lacks exclusion criteria, and as a consequence, it is easier for a person with a primary psychiatric diagnosis to be labeled as having SEID. Verrillo [9] also commented on these exclusionary SEID ambiguities, and then suggested that because major depression is not exclusionary, patients with a primary psychiatric disorder might be included in the SEID classification. These publications were only commentaries and did not provide data, so it is still unclear whether the SEID case definition [1] could inappropriately include cases of purely affective disorders, such as Major Depressive Disorder (MDD). It is also unclear whether SEID is more common within other autoimmune illnesses such as MS and Lupus. The present study evaluated whether the SEID case definition distinguished between persons with MDD, and other illnesses, using archival data that were available. We used data from four distinct studies, each with different case ascertainment methods, so we could begin to determine how the new SEID criteria might affect a variety of samples representing tertiary care settings, community based settings, as well as more patient self-diagnosed samples. We hypothesized that individuals with a number of formerly exclusionary illnesses would meet the SEID case definition, thus possibly increasing the prevalence rate of this illness.

2. Methods

2.1. Study 1

2.1.1. Procedure

In the first study, a CFS screening questionnaire had a combination of existing and new measures including: (1) several demographic related items; (2) The Fatigue Scale [10]; and (3) a list of symptoms associated with CFS. Interviewees were asked a series of questions that assessed whether or not they had a number of symptoms commonly experienced by people with CFS. The symptoms needed to be experienced for 6 or more months. The questions were asked by interviewers (for more details of this study, see [11]).

2.1.2. Participants

A total of 60 individuals (15 with CFS, 15 Controls, 15 with Multiple Sclerosis (MS), and 15 with Lupus) were recruited from the greater Chicago area for the present study. Fifteen of the participants were diagnosed by a physician in Chicago with experience in diagnosing and treating CFS. Each of these participants met the Fukuda et al. [2] definition of CFS. To be diagnosed with the CFS Fukuda et al. [2] criteria, participants had to experience persistent or relapsing fatigue for a period of six or more months concurrent with at least four of eight somatic symptoms that do not predate the fatigue. These symptoms are: sore throat, lymph node pain, muscle pain, joint pain, post-exertional malaise, headaches of a new or different type, memory and concentration difficulties, and unrefreshing sleep. Participants also needed to experience substantial reductions in occupational, educational or personal activities as a result of the illness and must not have any exclusionary medical or psychiatric illnesses.

Fifteen healthy control participants had not been diagnosed with CFS or any other illness that could cause significant fatigue. These participants had also been seen by a physician, and no illnesses that could cause fatigue were found (e.g., unresolved cases of hepatitis C virus infection, untreated hypothyroidism).

In addition, fifteen participants with a diagnosis of Multiple Sclerosis (MS) were recruited from self-help groups in the Chicago area. Each of these participants met Poser et al.’s [12] criteria for definite MS. Participants with other chronic medical conditions in addition to MS were excluded. Finally, fifteen participants with a diagnosis of Systemic Lupus Erythematosus (SLE) were recruited from self-help groups in the Chicago area. The participants with Lupus had to meet the SLE criteria as defined by the American Rheumatology Association [13]. There were no significant differences between groups with respect to race, age, education, marital status, and occupation. However, there were significantly fewer women in the healthy control group as compared to the other groups, and significantly more people were on disability in the CFS and MS group compared to the healthy control group.

2.1.3. SEID Diagnosis

To meet the SEID criteria [1] within this sample, a patient needed to have 6 or more months of illness. To meet the substantial reduction from previous levels of functioning criteria, a patient would have needed to have 6 or more months of substantial reduction in functioning. To meet the post-exertional malaise criteria, a patient would need to have indicated presence of at least 1 of our two post-exertional malaise symptoms: sickness/fatigue for >24 h after exercising or experiencing high levels of fatigue after everyday activity. To meet the unrefreshing sleep criteria, a patient would need to indicate unrefreshed sleep that is more frequent than their pre-illness levels. In order to meet the cognitive impairment criteria, a patient would need at least one of the following cognitive items: difficulty concentrating, difficulty finding the right word to say, difficulty with memory, or difficulty remembering things. Due to a lack of items that tapped into orthostatic intolerance criteria, patients would instead need to meet the cognitive impairment criteria to qualify for the SEID criteria. In another study, we found the option to have orthostatic intolerance instead of cognitive impairment typically enabled only approximately 2% more participants to meet SEID criteria [14].2.1.4. Results

As indicated in Table 1, 100% (n = 15) of those in the CFS group met the SEID criteria, whereas 47% (n = 7) in the Lupus group, 33% (n = 5) in the MS group, and 0% in the control group met the SEID criteria. In an effort to compare this new SEID case definition to the older Fukuda et al. [2] criteria, we computed the sensitivity and specificity. The SEID criteria evidenced a sensitivity of 1.0 (indicating that 100% of participants with CFS were correctly identified by the SEID criteria) and a specificity of 0.73 (indicating that 27% of participants without CFS were classified as meeting the SEID criteria).

Table 1. CFS, MS, Lupus, and Control Sample n = 60.

Diagnosis Percent Who Qualify for SEID

CFS (n = 15) 100% (n = 15)

MS (n = 15) 33% (n = 5)

Lupus (n = 15) 47% (n = 7)

Control (n = 15) 0% (n = 0)

2.2. Study 2

2.2.1. Procedure

In the second study, participants were screened by a trained interviewer to determine if they met the inclusion and exclusion criteria for CFS, MDD, or healthy controls (for more details, see [15]). As part of this screening process, all participants were administered the SCID-IV [16] to assess for psychiatric conditions. Participants who met criteria for participation were asked to complete a battery of questionnaires that measured demographics, social, emotional, and physical functioning, activity level, depression, and a comprehensive list of physical, cognitive, and emotional symptoms. Participants were asked to provide data for fatigue and the 8 diagnostic symptoms specified by the Fukuda et al. [2] case definition. They were asked to report if each symptom had been present for 6 months or longer, began before the onset of their fatigue or health problems, how often it was experienced, and rated the intensity of each symptom on the same scale of 0 to 100. A prior study by King and Jason [17] found that the CFS group against the MDD and control group had significant differences for the following items rated on severity: 4 symptoms in the fatigue/weakness group (fatigue, post-exertional malaise, muscle weakness, need to nap each day), 3 symptoms in the neuropsychological category (frequently losing train of thought, difficulty finding the right word, confusion/disorientation), 4 symptoms in the infectious category (sore throat, tender lymph nodes, hot and cold spells, feeling chilled/shivery), 3 symptoms in the rheumatologic category (muscle pain, pain in multiple joints without swelling, night sweats), 1 symptom in the cardiopulmonary category (shortness of breath), 1 symptom in the neurological category (blurred vision) and unrefreshing sleep. Therefore, these items were also used in the present study.

The Structured Clinical Interview for the DSM-IV (SCID) is a valid and reliable semi-structured interview guide that closely resembles a traditional psychiatric interview [16]. The SCID is designed to identify current, past, and lifetime (chronic or recurring, current and past) diagnoses for a majority of DSM-IV, Axis I psychiatric disorders. The SCID is commonly administered during a single session lasting 45 min to an hour. Diagnostic decisions generated by the SCID are based on all possible sources of historical, symptomatic, and behavioral information. The SCID begins with a semi-structured interview portion designed to yield a tentative diagnosis. The tentative diagnosis is then systematically assessed during the structured portion of the interview through the use of embedded questions that conform to the exact, Axis I criteria set forth by the DSM-IV.

The SF-36 is 36-item instrument that is comprised of multi-item scales that assess physical functioning, role limitations, social functioning, bodily pain, general mental health, vitality, and general health perceptions. Higher scores indicate better health, lower disability, or less impact of health on functioning.

Reliability and validity studies have demonstrated that the 36-item version of the SF-36 has high reliability and validity in a wide variety of patient populations [18].

2.2.2. Participants

A total of 45 individuals (15 with CFS, 15 with MDD, and 15 healthy controls) were recruited from the greater Chicago area [15]. Fifteen participants with CFS were solicited to participate in the present study. Participants were drawn from two sources, a local CFS support group in Chicago and previous research studies conducted at DePaul University. Participants were required to have been diagnosed with CFS, using Fukuda et al.’s [2] diagnostic criteria, by a Board-certified physician and were required to have a current (active) case of CFS. All participants had been seen by their physician in the past year. Individuals who reported having uncontrolled or untreated medical illnesses (e.g., untreated anemia) were excluded.All participants were screened with the SCID-IV to ensure that they did not have any exclusionary psychiatric illnesses as stipulated by the Fukuda et al. [2] case definition.

Fifteen participants with a diagnosis of MDD were solicited from a local chapter of the National Depressive and Manic Depressive support group in Chicago. Participants were required to have been diagnosed with major depression by a licensed psychologist or psychiatrist. All participants were screened with the SCID-IV to ensure that they met criteria for a current (active) case of major depression and did not have any other current psychiatric illnesses. Individuals who had other current psychiatric conditions in addition to major depression were excluded. Individuals who reported having uncontrolled or untreated medical illnesses (e.g., anemia, diabetes) were also excluded. In the MDD group, all 15 (100%) participants met DSM-IV diagnostic criteria for MDD. None of the participants in the MDD group met criteria for MDD with catatonic, melancholic, psychotic, or atypical features. Participants in the MDD group did not meet criteria for any other Axis I disorders.

Finally, fifteen healthy control participants were solicited from the greater Chicago area. Individuals who did not have any medical illnesses or who did not have any uncontrolled or untreated illnesses (e.g., anemia, diabetes) were allowed to participate. All participants were screened with the SCID-IV to ensure that they did not have any current psychiatric illnesses. Individuals with current psychiatric conditions were excluded. Sociodemographic data were compared across the three groups, and there were no significant differences with respect to gender, race, age, SES, education, marital status, occupation, work status, and additional roles [15].

2.2.3. SEID Diagnosis

To meet the SEID criteria [1] within this sample, a patient would need to have 6 or more months of fatigue. Because the SEID criteria do not indicate how to assess substantial reductions, we used criteria that has been published in prior studies with specified cut off points [6,14]. To meet substantial reduction from previous levels of functioning criteria, a patient needed to meet 2 of the following 3 SF-36 criteria: role physical <50, social functioning <62.5, or vitality <35. To meet the post-exertional malaise criteria, a patient needed to have 6 or more months of post-exertional malaise. To meet the unrefreshing sleep criteria, a patient needed to have 6 or more months of unrefreshing sleep. To meet the SEID criteria, the individual needed to have either a cognitive impairment or orthostatic intolerance symptom. In order to meet the cognitive impairment criteria, a patient would need at least one of the following cognitive items: impaired memory present for 6 months or longer, slowness of thought, absent mindedness or forgetfulness, or difficulty focusing. To meet the orthostatic intolerance criteria, a patient would need presence of at least one of the following items: dizziness, wobbling feet when getting up.

2.2.4. Results

As indicated in Table 2, 93% (n = 14) of those in the CFS group, 27% (n = 4) in the MDD group, and 0% in the control group met SEID criteria. In an effort to compare this new SEID case definition to the older Fukuda et al. [2] criteria, we computed the sensitivity and specificity. These criteria resulted in a sensitivity of 0.93 and a specificity of 0.86.

Table 2. CFS vs. MDD Database n = 45.

Diagnosis Percent Who Qualify for SEID

CFS (n = 15) 93% (n = 14)

MDD (n = 15) 27% (n = 4)

Control (n = 15) 0% (n = 0)

2.3. Study 3

2.3.1. Procedure

The data were derived from a larger community-based study of CFS that was carried out in three stages [3]. Stage 1 entailed a cross-sectional screening telephone survey of a random sample of 28,673 households, with 18,675 adults completing the screening interview (65.1% completion rate). Of these participants, 780 (4.2%) of the respondents had six or more months of fatigue. Stage 2 involved a structured psychiatric interview for a sample of those respondents from Stage 1 who screened positive for a CFS-like syndrome based on the Fukuda et al. [2] criteria, as well as a screen negative control sample.

According to the Phase 1 screen, of the 18,675 interviewees, 16,453 (88%) had no prolonged or chronic fatigue, 1435 (7.7%) had prolonged fatigue, and 780 (4.2%) had chronic fatigue (seven cases refused to answer the fatigue questions). Among those 780 respondents with chronic fatigue, at Phase 1; 304 had ICF-like illness (e.g., not enough minor symptoms to be eligible for a CFS diagnosis), 68 had a CF-explained-like condition, and 408 had CFS-like profiles. All 408 members of the CFS-like group were invited to participate in Phase 2. Of this group of 408 individuals with CFS-like symptoms, the physician review team reviewed data on 166 individuals, who provided data during the Phase 2 evaluation.

There were 47 individuals who were evaluated in a control group, and these individuals screened negative for CFS-like illness during Phase 1.

A team of four physicians and a psychiatrist were responsible for making a final diagnosis with two physicians independently rating each file using the current U.S. case definition of CFS [2]. Where physicians disagreed, a third physician rater was used [3]. Table 3 shows the number of cases in the control group (Control), individuals who were diagnosed with CFS using the Fukuda et al. [2] case definition (CFS), Idiopathic chronic fatigue (ICF, individuals who did not meet all the Fukuda criteria), and chronic fatigue explained (CF, i.e., melancholic depression, bipolar disorders, anorexia nervosa/bulimia nervosa, psychotic disorders, drug or alcohol related disorders, or medical explanations for their fatigue).

Table 3. Community Epidemiology database n = 213.

Diagnosis Percent Who Qualify for SEID

CFS (n = 32) 75% (n = 24)

ICF (n = 45) 44% (n = 20)

CF (n = 89) 47% (n = 42)

Control (n = 47) 6% (n = 3)

2.3.3. SEID Diagnosis

To meet the SEID criteria [1] within this data set, a patient would need to have one of the following indications of 6 or more months of fatigue: fatigue for 6 or more months or fatigue present for more than 50% of the time for a minimum of 6 consecutive months. To meet substantial reduction from previous levels of functioning criteria, a patient needed to meet 2 of the following 3 criteria: role physical <50, social functioning <62.5, or vitality <35. To meet the post-exertional malaise criteria, a patient needed to report the occurrence of one of the following symptoms: prolonged generalized fatigue or malaise following previously tolerable levels of exercise, feeling generally worse than usual or fatigued for 24 h or more after exercise, or exercise brings on my fatigue. To meet the unrefreshing sleep criteria, a patient needed one of the following symptoms: after a night of sleep do you feel rested, after a night of sleep does your fatigue go away temporarily, needing to nap daily, problems falling/staying asleep. To meet the SEID criteria, the individual needed to meet either the cognitive impairment or orthostatic intolerance symptom. In order to meet the cognitive impairment criteria, a patient would need presence of at least one of the following cognitive items: forget recent conversations and events, confusion or distortion in familiar places, inability to concentrate, difficulty retaining information, only able to focus on one thing at a time, or new trouble with math. To meet the orthostatic intolerance criteria, a patient would need presence of at least one of the following items: sharp shooting pains in chest, rapid heartbeat, feeling unsteady on feet, often feeling dizzy, feeling weak or dizzy right after standing up.

2.3.4. Estimating SEID Prevalence

Prevalence, which is the number to be estimated, is represented by P (p). The total number of respondents screened in Phase 1 (18,668) is N (Nt). The proportion of screened positives (408/18,668 = 0.0219) is PI (π), and the proportion of screened negatives (18,260/18,668 = 0.9781) is 1 − PI (1 − π). The proportion of screened positives evaluated in Phase 2 who were diagnosed with SEID (Number of cases with SEID/166) is L1 (λ1), and the proportion of screened negatives evaluated in Phase 2 who were diagnosed with SEID (0/47 = 0.0) is L2 (λ2).

2.3.5. Results

As indicated in Table 3, 75% (n = 24) of those in the CFS group met the SEID criteria, whereas 47% (n = 42) for the CF group, 44% (n = 20) for the ICF group, and 6% (n = 3) for the controls. Within the Chronic Fatigue explained by medical or psychiatric illness (CF), of those 19 with Melancholic Depression, 47% (n = 9) met the SEID criteria. In addition, for those with a medical reason for their fatigue, 48% (n = 16) met SEID criteria. In an effort to compare this new SEID case definition to the older Fukuda et al. [2] criteria, we computed the sensitivity and specificity. In this sample, the SEID criteria had a sensitivity of 0.75 and a specificity of 0.64.

This data set had been previously used to estimate the prevalence of CFS [3], which was 0.42. With the new number of SEID cases, we recalculated the prevalence rate, using methods described elsewhere [19].

We solicited participants with a diagnosis of MDD and CFS to participate in this study [20]. We administered to all participants the CDC Symptom Inventory, which assesses information about the presence, frequency, and intensity of 19 fatigue related symptoms during the past one month [21]. All eight of the critical Fukuda et al. [2] symptoms were included as well as 11 other symptoms (e.g., diarrhea, fever, sleeping problems, nausea, etc.). For each of the eight Fukuda et al. [2] symptoms, participants were asked to report the frequency (1 = a little of the time, 2 = some of the time, 3 = most of the time, 4 = all of the time) and severity (the ratings were transformed to the following scale: 0.08 = very mild, 1.6 = mild, 2.4 = moderate, 3.2 = severe, 4 = very severe). The frequency and severity scores were multiplied for each of the eight critical Fukuda et al. [2] symptoms and were then summed, in order to determine whether a person met the Fukuda et al. [2] criteria, as operationalized by Reeves et al. [22].

2.4.2. Participants

We recruited 64 individuals, 27 with CFS and 37 with MDD. We obtained our sample of participants with CFS from two sources, local CFS support groups in Chicago and a previous research study conducted at DePaul University. To be included in the study, participants were required to have been diagnosed with CFS, using the Fukuda et al. [2] diagnostic criteria, by a certified physician and were required to currently meet CFS criteria using the Fukuda et al. criteria. We excluded individuals who had other current psychiatric conditions in addition to major depression or who reported having untreated medical illnesses (e.g., diabetes, anemia).

For the MDD group, we found participants from three sources, local chapters of the Depression and Bipolar Support Alliance group in Chicago; Craigslist—a free local classifieds ad forum that is community moderated; and online depression support groups. To be included in the study, all participants were required to have been diagnosed with a MDD by a licensed psychologist or psychiatrist. We excluded individuals who had other current psychiatric conditions in addition to a MDD (e.g., bipolar, schizophrenia) or who reported having untreated medical illnesses were also excluded. We carefully screened participants to ensure that participants from the MDD group did not have CFS as defined by the Fukuda et al. [2] criteria.

2.4.3. SEID Diagnosis

To meet the SEID criteria [1] within this sample, a patient needed to have 6 or more months of illness. To meet substantial reduction from previous levels of functioning criteria, a patient needed to meet 2 of the following 3 criteria: role physical <50, social functioning <62.5, or vitality <35. To meet the post-exertional malaise criteria, a patient would need to have a frequency of at least some of the time and severity score of at least moderate to indicate prolonged levels of malaise following previously tolerated exercise. To meet the unrefreshing sleep criteria, patients would have to have indicated at least 1 of the unrefreshing sleep symptoms: Unrefreshing sleep in the past month, unrefreshing sleep present 6 months or longer, or trouble sleeping through falling or staying asleep. In order to meet the cognitive impairment criteria, a patient would need to have a frequency of at least some of the time and severity score of at least moderate to indicate impaired concentration. Due to a lack of items that tapped into orthostatic intolerance criteria, patients would instead need to meet the cognitive impairment criteria to qualify for this measure. In a prior study by Jason, Sunnquist, Kot, Brown, Newton et al. [14], when using the option to have orthostatic intolerance instead of cognitive impairment, only an additional 2% of participants meet the SEID criteria [14].

2.4.4. Results

As indicated in Table 4, 81% (n = 22) of those in the CFS group met the SEID criteria, whereas 24% (n = 9) of those in the MDD group met SEID criteria. In an effort to compare this new SEID case definition to the older Fukuda et al. [2] criteria, we computed the sensitivity and specificity. The SEID criteria resulted in a sensitivity of 0.81 and a specificity of 0.76.

Table 4. CFS vs. MDD Database n = 64.

Diagnosis Percent Who Qualify for SEID

CFS (n = 27) 81% (n = 22)

MDD (n = 37) 24% (n = 9)

3. Discussion and Conclusions

Tables 1–4 indicate that the SEID criteria will probably select few individuals from healthy control samples, and although a few controls were identified as meeting SEID in Table 3, that control sample included a large group of individuals from the community, many of whom did have varying levels of fatigue and other problems. In addition, it appears that the SEID criteria do identify most of those who met the Fukuda criteria, as evidenced by the generally high sensitivity statistics; however, rates tend to be lower in Table 3, which is a community rather than tertiary sample, where symptom rates tend to be lower. Most importantly, the SEID criteria do tend to identify high rates of those with other medical illnesses, as indicated in Tables 1 and 4 and the low specificity levels, and therefore many individuals with autoimmune and other health illnesses that had been exclusionary with prior case studies will now be comorbidity. In addition, as indicated in Tables 2 and 4, many individuals with a purely affective disorder will now be also classified as having SEID.

Rates of SEID could increase due to the reduction of many exclusionary criteria. Based on study 3, using the Jason et al. [3] community-based epidemiologic study, 32 individuals had been classified as meeting the Fukuda et al. [2] criteria, for a prevalence rate of 0.42, but we estimate that 89 from this sample would now meet the SEID criteria, for a prevalence rate of 1.17, thus, the SEID prevalence rate would be 2.8 times as great. Of course, if our samples had only included those who had been selected patients had met the Fukuda et al. [2] criteria, as occurred in a recently published study [14], then those with many medical and psychiatric illnesses would have already been excluded, so in a study comprised of just those meeting the Fukuda et al. [2] criteria, the rates of those meeting the SEID criteria would be much more comparable to those meeting the CFS Fukuda criteria [14].

The current study suggests that the core SEID symptoms are not unique to SEID, as some patients with other illnesses, such as those evaluated in this study, have comparable symptoms. As a consequence, some patients with illnesses that had previously been exclusionary under past case definitions such as Fukuda et al. [2] will now be comorbid, possibly leading to an expanded number of individuals meeting SEID criteria. Even though the SEID criteria are for a clinical case definition [1], rather than a research case definition, it is likely that it will be used for research by investigators, as a similar process occurred with the clinical Fukuda et al. [2] CFS criteria. If there are ambiguities with case definitions, like what has occurred with the Fukuda et al. [2] CFS criteria, there will be difficulties in replicating findings across different laboratories, estimating the prevalence of the illness, consistently identifying biomarkers, and determining which treatments help patients. To develop or validate a reliable case definition, we need to both provide operationally explicit inclusionary and exclusionary criteria as well as develop a consensus within the scientific community for the case definition.

The current study suggests that some patients with MDD, who also have chronic fatigue, sleep disturbances, and poor concentration, will be misdiagnosed as having SEID. MDD can occur for anyone with a serious medical illness. Some patients might have been depressed prior to becoming ill with SEID, and probably others as a reaction to this illness [23]. However, patients with CFS have symptoms including night sweats, sore throats, and swollen lymph nodes, that are not commonly found in depression, and illness onset with CFS is often sudden, occurring over a few hours or days, whereas primary depression generally shows a more gradual onset [24,25]. Hawk, Jason, and Torres-Harding [15] were 100% successful in differentiating patients with CFS and MDD using the following variables: percent of time fatigue was reported, post-exertional malaise severity, unrefreshing sleep severity, confusion/disorientation severity, shortness of breath severity, and self-reproach.

Mood disorders are the most prevalent psychiatric disorders after anxiety disorders: for major depressive episode, the one-month prevalence is 2.2%, and lifetime prevalence is 5.8% [26]. The erroneous inclusion of people with primary psychiatric conditions in SEID samples would have detrimental consequences for the interpretation of epidemiologic, etiologic, and treatment efficacy findings for people with this illness. This is what occurred with another CFS case definition developed by the CDC [22]. Jason et al. [19] found that 38% of those with a diagnosis of a MDD were misclassified as having CFS using the CDC empirical case definition of Reeves et al. [22]. Fortunately, few adopted the Reeves et al. [22] empiric case definition, but the IOM [1] has considerably more prestige and influence, so their proposed SEID case definition criteria could ultimately have more far reaching effects. In study 3, 47% of those with Melancholic Depression met SEID criteria, whereas rates of MDD meeting SEID criteria in studies 2 and 4 were 27% and 24%, respectively. If individuals with primary affective disorder are misdiagnosed with SEID and provided cognitive behavioral treatment, they will more likely have positive outcomes, and this may create more difficulties in understanding the effects of these interventions for those who have ME (Myalgic Encephalomyelitis). Price, Mitchell, Tidy and Hunot [27] reviewed 15 studies of CBT with a total of 1043 participants with CFS. At treatment’s end, the CBT group showed more clinical improvement in contrast to those in usual care, but changes were not maintained at a one- to seven-month follow-up when including patients who had dropped out.

There are additional aspects of the IOM [1] case definition that have problems, besides exclusionary criteria. For example, it is unfortunate that there was a lack of a recommendation for a mental health evaluation, or a structured clinical interview, especially as some of these symptoms can overlap with primary affective or mood disorders. The SEID criteria require a patient to have either cognitive impairment or orthostatic illness, but orthostatic intolerance does not evidence prevalence rates as high as the other proposed core symptoms, whereas cognitive impairment does have higher prevalence rates [28]. Also, factor analytic studies do not support this system of a choice of cognitive impairment vs. orthostatic intolerance [29].

We believe this report did not adequately deal with the issue of whether distinct categories or continuous measures best capture patient differences, as there well might be different groupings of patients, with some having different features or more severity.

Finally, empirical methods could have been employed to test the proposed classification system, and the committee members might have benefited from testing out their proposed model with an actual data set, as has recently been done [14].

There are a number of limitations in the present study. As we used archival data sets, some of the questions that have been proposed to define SEID were not available. Clearly, the current study needs to be replicated with questions that are now proposed [7], however, our questionnaires were able to assess that vast majority of issues and domains within SEID. In addition, several of our samples were relatively small, so larger studies are needed. Furthermore, we were only able to identify data sets representing a few illnesses, and more illnesses need to be investigated to assess whether some patients with these diagnoses might be included within the SEID classification system. It should be noted that samples recruited from patient organizations or that do not have an independent physician work up and diagnosis might be less reliable. The new SEID [1] criteria suggest frequency and severity ratings, many of which were not available from the data sets reported in the current study, so it is possible that some occurrence ratings selected less impaired individuals and inflated the number of patients meeting SEID criteria.

Finally, none of the studies included a two-day exercise challenge, and such a test would be a better approach for documenting post-exertional malaise. However, such a test might exclude some of the individuals from a SEID diagnosis, and given that the SEID is a clinical criteria, most medical practitioners will not have access to this expensive two-day exercise test in the diagnostic process.

The recent IOM report [1] is being widely discussed among academics and the patient community [30]. There is a need to also consider how these recommendations will affect patients in other countries, given the prestige associated with an IOM report. The present study suggests that there might be a number of illnesses that had been exclusionary, which now might now be considered comorbid. This is a complex diagnostic decision, and there probably is a need for clearer rules regarding whether a person has an exclusionary or comorbid illness. Ultimately, we need investigations to help point to implications of using these new criteria, and ultimately, we need an open and inclusive process where all parties, including key gatekeepers including the patients, scientists, clinicians and government officials, are involved in the decision making process.

Author Contributions

All authors contributed to the conceptualization of the study, the data analysis, and the writing of this article.

In the following commentary, Leonard Jason defends the use of self-reporting measures for the diagnosis of ME/CFS. While self-reporting has its merits, it also has drawbacks (e.g. human error). Nevertheless, Jason's comments about the IOM's new definition should be given serious consideration.

Jason is correct in pointing out that the new IOM criteria will capture patients with a number of other illnesses, especially now that there are no exclusionary diagnoses. Neuroborreliosis, an infection of the CNS by the Lyme disease bacteria of the genus Borrelia is indistinguishable from ME. (That is because inflammation in the CNS is common to both.) Lyme disease, including neuroborreliosis, would fit the new definition, as would Gulf War Illness, many autoimmune diseases, heart failure, and major depression.

Given that autoimmune diseases such as lupus and Hashimoto's are hard to detect, and that illnesses such as GWI and major depression have no confirmatory tests, it is likely that the IOM definition will result in exactly what it purported to change - a vague, overly broad diagnostic tool that will result in skewed research results and inappropriate treatment recommendations.____________________

Twisk (2015) first suggested that there was an assumption in the article by Jason et al. (2015) that myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are identical illnesses. This was neither stated nor endorsed in Jason et al. (2015). In fact, my position on this issue is rather different from what this reviewer suggested, and my position is also different from the recent announcement by the Institute of Medicine (IOM, 2015a, p. 45) regarding the newly defined systemic exertion intolerance disease (SEID), where “the committee uses the umbrella term ‘ME/CFS’ to refer to ME and CFS throughout this report”. In contrast, in the Jason et al. (2015) article, each of these terms refers to a different case definition, with CFS referring to Fukuda et al. (1994), ME/CFS referring to Carruthers et al. (2003), and ME-ICC (International Consensus Criteria) referring to Carruthers et al. (2011). The article by Jason et al. (2015) identified a sample that had been diagnosed by a licensed physician using either the Fukuda et al. (1994) CFS or Carruthers et al. (2003) ME/CFS case definitions. Twisk (2015) mentions that it is not possible to draw conclusions regarding “the” illness because some individuals within this sample met different criteria (CFS, ME/CFS, or ME-ICC).

However, if an investigator desires to compare those who meet a more liberal criteria, such as with CFS, to those that meet a more specific criteria, such as with ME-ICC or the four empiric items identified in Jason et al. (2015), then it is critical to have a larger, more varied sample that represents both groups. In other words, to identify different groups of patients, which is what was found in the article, then a larger, more heterogeneous sample is required. In fact, our article did find that those who met the more specific four-item empiric criteria had significantly more symptoms and impairment than those that did not.

This approach to identify different types of patients becomes even more important with the new IOM (2015a) position on exclusionary conditions for SEID. Within IOM’s SEID Report Guide for Clinicians (IOM, 2015b, pp. 4), it states: “The presence of other illnesses should not preclude patients from receiving a diagnosis of ME/CFS (SEID) except in the unlikely event that all symptoms can be accounted for by these other illnesses.” The word “unlikely” conveys the impression that most other illnesses would be considered comorbid (and not exclusionary) as they probably would not account for the unique SEID symptoms.

The problem for diagnosticians in interpreting these guidelines is that the core IOM symptoms are not unique to SEID, as other illnesses have comparable symptoms (e.g. cancer, Hashimoto’s, lupus, chronic heart failure, multiple sclerosis, etc.). So, many illnesses that had previously been exclusionary under past case definitions will now be comorbid, leading to an expanded number of individuals meeting SEID criteria. This will be particularly problematic for those with primary affective disorders, who could be now be diagnosed as having SEID. If individuals with primary affective disorder are misdiagnosed with SEID and provided cognitive behavioral treatment, they will more likely have positive outcomes. These outcomes would then create more difficulties in understanding the effects of these interventions for those who have ME.

Some patients with major depressive disorder also have chronic fatigue, sleep disturbances, and poor concentration; therefore, it is possible that some patients with a primary affective disorder could be misdiagnosed as having SEID. However, ME symptoms including night sweats, sore throats, and swollen lymph nodes are not commonly found in depression. Furthermore, illness onset with ME is often sudden, occurring over a few hours or days, whereas primary depression generally shows a more gradual onset. Hawk, Jason, and Torres-Harding (2006) used discriminant function analyses to identify variables that successfully differentiated patients from those with major depressive disorder and controls. Using percent of time fatigue was reported, post-exertional malaise severity, unrefreshing sleep severity, confusion/disorientation severity, shortness of breath severity, and self-reproach to predict group membership, 100% were classified correctly.

Mood disorders are the most prevalent psychiatric disorders after anxiety disorders: for major depressive episode, the one-month prevalence is 2.2% and lifetime prevalence is 5.8% (Regier, Boyd, & Burke, 1988). If the SEID criteria now include people with primary psychiatric conditions, a rather large percent of those diagnosed with SEID will be from this group, so it is now even more important to differentiate these individuals from those that have ME, or those with more severe symptoms and disability, such as what occurred in the Jason et al. (2015) four-item empiric criteria. About a decade ago, a prior CFS case definition was developed by the Centers for Disease Control and Prevention (CDC) (Reeves et al., 2005) which considerably increased prevalence rates of CFS. Yet, these findings were challenged by Jason, Najar, Porter, and Reh (2009), who found that 38% of those with a diagnosis of a major depressive disorder were misclassified as having CFS using the CDC empirical case definition of Reeves et al. (2005). Fortunately, few adopted the Reeves et al. (2005) empiric case definition, but the IOM (2015a) has considerably more prestige and influence, so their proposed SEID case definition criteria could ultimately have more far reaching effects.

Another issue brought up by Twisk (2015) was that our questionnaire omitted Ramsay’s (1988) essential ME criteria – muscle fatigability and prolonged muscle weakness. Therefore, Twisk (2015) stated, if our sample had been represented by patients with ME, we would have found that 100% of them would have had muscle weakness and muscle fatigability. Twisk (2015) implied that our sample did not have this important characteristic. In fact, 100% of the patients who were identified by our four-item empiric criteria indicated that they were “Physically drained/sick after mild activity”. Although it is true that our questionnaire did not assess Ramsay’s muscle fatigability, we did include the following items: “Muscle weakness”, “Physically drained/ sick after mild activity”, “Minimum exercise makes you physically tired”, “Next-day soreness after non-strenuous activities”, and “Dead, heavy feeling after starting to exercise”, and these items were among the best discriminators of patients versus controls. The primary goal of this article was to identify symptoms with strong discriminatory power to distinguish patients from controls; muscle weakness was more prevalent among healthy controls than the symptom “physically drained/sick after mild activity”.A third issue brought up by Twisk (2015) was that the presence of symptoms should be assessed with objective measures, rather than just self-report items. However, if self-report measures are highly correlated with these markers, then they represent less expensive methods to conduct initial evaluations. Those identified by less expensive self-report questionnaires could then be more rigorously evaluated during comprehensive medical examinations, and with a variety of more objective measures. For example, Jason, Brown, Evans, and Brown (2012) found that TH2 shift and impairment to the immune system among patients was associated with self report measures, and Tryon, Jason, Frankenberry, and Torres-Harding (2004) found continuous waist activity provide evidence of a blunted circadian rhythm in patients.

With the recent IOM (2015a) report, it is even more importance to conduct studies to determine whether distinct categories or continuous measures best capture patient differences, and such investigations can and should be addressed by employing both large data sets and sophisticated research methods. Ultimately, we need an empiric, collaborative, open, interactive, and inclusive process to make recommendations regarding specific aspects of the case definitions, where all parties, including key gatekeepers including the patients, scientists, clinicians, and government officials, are involved in the decision-making process.

Disclosure statement: No potential conflict of interest was reported by the author.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/ licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Below is a message from Kristina Bray, who has launched a petition calling on the IOM to cease any attempts to rename ME as SEID (systemic exertion intolerance disease).

Kristina argues that the new name does not express the complexity of the disease and, as a consequence, will not be taken seriously by physicians.

These are good arguments. In addition, it needs to be pointed out that "exertion intolerance" is a new term. Medical professionals are not familiar with it, and, more importantly, insurance companies do not include it on their roster of conditions that can be tested for. Exercise intolerance, on the other hand is familiar to both physicians and insurance companies. It is, however, not specific to ME/CFS, and therefore is fairly useless as a description.

Dr. Clayton has responded to the objections raised against the term SEID by saying that SEID could be used in addition to CFS and ME, each one of which would have its own definition. Clayton's solution would make it impossible for anyone to diagnose this illness - which defeats the whole purpose of the million-dollar IOM study.

Do we really need yet another acronym? Why not simply do away with CFS, and replace it with a name that has historic continuity, for example, ME? And wouldn't it have been more efficient to adopt the criteria that specialists have already devised for the illness (the CCC) rather than reinvent the wheel? _______________________

By Kristina Bray

As sufferers of, carers for or supporters of people suffering from the debilitating neurological illness M.E. (Myalgic Encephalomyelitis) we call upon the IOM (Institute of Medicine) to cease any attempts to have M.E renamed as S.E.I.D.

As people with first hand experience of the horrors of ME we do not feel that "Systemic Exertion Intolerance Disease" in any way expresses the severity, complexity nor the full impact that ME has on those who suffer from it.

Indeed, we feel that changing the name will hinder, rather than help people in seeking proper diagnosis and/or medical support and could also undermine attempts to raise awareness of this serious and chronic condition among the general public.

Sufferers of ME need awareness, support and treatment in the short term and research over the longer term to give them the best possible chance of achieving improvement, they do not need a "re branding" exercise that can do nothing to tackle the real struggles faced by people with ME.

The IOM Report, "Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness" was released on Tuesday February 10, 2015.

(You can read and/or download the report as well as watch the video of the announcement HERE. You can get the gist of the report by reading the Summary at the beginning, or Recommendations on page 209.)

Much like its previous report on Gulf War Illness, the IOM's report on ME/CFS has generated a tremendous amount of media coverage (Time, CBS, NY Times Blog, ABC), as well as spirited discussion in the ME/CFS community. While mainstream organizations have welcomed the report's emphasis on the serious nature of the disease, there are some lingering doubts about the appropriateness of the new name, "systemic exertion intolerance disease" (SEID), as well as the viability of the new definition.

The report made four recommendations:Recommendation 1: Physicians should diagnose myalgic encephalomyelitis/chronic fatigue syndrome if diagnostic criteria are met following an appropriate history, physical examination, and medical work-up. A new code should be assigned to this disorder in the International Classification of Diseases, Tenth Edition (ICD-10), that is not linked to “chronic fatigue” or “neurasthenia.”Recommendation 2: The Department of Health and Human Services should develop a toolkit appropriate for screening and diagnosing patients with myalgic encephalomyelitis/chronic fatigue syndrome in a wide array of clinical settings that commonly encounter these patients, including primary care practices, emergency departments, mental/behavioral health clinics, physical/occupational therapy units, and medical subspecialty services (e.g., rheumatology, infectious diseases, neurology).Recommendation 3: A multidisciplinary group should reexamine the diagnostic criteria set forth in this report when firm evidence supports modification to improve the identification or care of affected individuals. Such a group should consider, in no more than 5 years, whether modification of the criteria is necessary. Funding for this update effort should be provided by nonconflicted sources, such as the Agency for Healthcare Research and Quality, through its Evidence-based Practice Centers process, and foundations.Recommendation 4: The committee recommends that this disorder be renamed “systemic exertion intolerance disease” (SEID). SEID should replace myalgic encephalomyelitis/chronic fatigue syndrome for patients who meet the criteria set forth in this report. [Italics mine throughout]

Some Background: The IOM's Charge

The IOM is an independent nonprofit organization founded in 1970. As health arm of the National Academy of Sciences, it works outside of the federal government to provide "unbiased and authoritative advice" to decision makers and the public. Because it is not part of the federal government, its decisions to not constitute policy. No branch of HHS is obliged to follow its recommendations.

In 2013, HHS contracted the IOM to evaluate the current criteria for diagnosis of ME/CFS and recommend clinical diagnostic criteria that would "address the needs of health care providers, patients, and their caregivers."

Specifically, the committee was asked to:

• conduct a study to identify the evidence for various clinical diagnostic criteria for ME/CFS using a process with input from stakeholders, including practicing clinicians and patients;

• develop evidence-based clinical diagnostic criteria for ME/CFS for use by clinicians, using a consensus-building methodology;

• recommend whether new terminology for ME/CFS should be adopted; and

• develop an outreach strategy for disseminating the new criteria nationwide to health professionals.

The committee was also asked to distinguish among disease subgroups, develop a plan for updating the new criteria, and make recommendations for the plan’s implementation.

With the exception of the CAA (now Solve ME/CFS Initiative) the immediate reaction to the million-dollar IOM contract was negative. Fifty of the world's leading experts in ME/CFS wrote a letter to then Secretary of HHS Kathleen Sebelius endorsing the Canadian Consensus Criteria (CCC) a definition based on "scientific knowledge gained from decades of research. " The letter also warned that the contract "would move ME/CFS science backward by engaging non-experts in the development of a case definition for a complex disease about which they are not knowledgeable." (You can read the letter HERE.) The letter was supported by hundreds of advocates, as well as petitions which garnered 10,000 signatures.

Analysis in a nutshell

Pros:

The report clearly states that ME/CFS is a complex a "serious, chronic, complex, multisystem disease that frequently and dramatically limits the activities of affected patients.

The report recommends abandoning the name "chronic fatigue syndrome."

The report recognizes that research funding has been inadequate.

Cons:

The report recommends a definition that is simplistic, undermining the statement that ME/CFS is a "complex, multi-system disease."

By limiting diagnosis to four or five non-specific symptoms, the IOM definition, like the Fukuda definition, will capture people without ME/CFS.

The core symptoms of the new diagnosis fit into the clinical definition for anxiety with depression.

Exertion intolerance has been, and will be, interpreted by physicians as a psychiatric manifestation of "fear avoidance" of exercise.

The name "systemic exertion intolerance disease" reduces ME/CFS to a single symptom.

The inclusion of "systemic" in the name is meaningless. All diseases are systemic.

Exclusionary diagnoses are no longer ruled out, which means patients with early MS, Hashimoto's, lupus, mitochondrial disease, Ehlers-Danlos and other treatable but hard-to-detect illnesses may receive a false diagnosis of SEID.

In-depth analysis of the report

The Good

Excellent overview of the research

On the whole, the report did a very good job of discussing the research pertaining to diagnosis, subgroups, symptoms clusters, as well as documenting key problems such as lack of funding for research, and inadequate coverage in medical schools. Anyone taking the time to read the entire report would have a clear view of the types of problems faced by the ME/CFS community. (One of those problems is the constant confusion between "chronic fatigue" and CFS, a problem which the IOM perpetuated by citing studies on "chronic fatigue.")

Abandonment of "chronic fatigue syndrome"

After a healthy discussion of all the reasons why CFS is a poor name for the disease, the IOM concluded that "the term 'chronic fatigue syndrome' often results in stigmatization and trivialization and should no longer be used as the name of this illness" (p 60). The report goes on to say that "ME/CFS should not be considered merely a point on the fatigue spectrum or as being simply about fatigue. [...] Other factors, such as orthostatic intolerance, widespread pain, unrefreshing sleep, cognitive dysfunction, and immune dysregulation, along with secondary anxiety and depression, contribute to the burden imposed by fatigue in this illness."

Recognition of 2-day CPET as an objective measure of ME/CFS

The IOM report recognizes PEM as one of the defining characteristics of ME/CFS (though the report also mentions that PEM is experienced by patients with MS and major depression). Citing the Keller and Snell studies, the report supported the 2-day CPET protocol "as an objective indicator that physical exertion may decrease subsequent function in some ME/CFS patients. By contrast, a single CPET may be insufficient to document the abnormal response of ME/CFS patients to exercise" (p 84).

Recognition of cognitive impairment and brain abnormalities

The IOM reviewed the past ten years of research on neurocognitive impairment and brain abnormalitites, and did a credible job of summarizing them. While the IOM did not draw any conclusions from the brain studies it examined (including th﻿e recent Nakatomi study on brain inflammation, but omitting the Stanford study) the committee did state that "There is sufficient evidence that slowed information processing is common in patients with ME/CFS, and a growing body of evidence shows that it may play a central role in overall neurocognitive impairment associated with the disease. Such a deficit may be responsible for the disability that results in loss of employment and loss of functional capacity in social environments" (p 106).

Recognition of immune dysfunction

After a review of NK cell toxicity and immune activation studies the IOM concluded that "Sufficient evidence supports the finding of immune dysfunction in ME/CFS" (p 153).

Acknowledgment of pediatric ME/CFS

"There is sufficient evidence that orthostatic intolerance and autonomic dysfunction are common in pediatric ME/CFS; that neurocognitive abnormalities emerge when pediatric ME/CFS patients are tested under conditions of orthostatic stress or distraction; and that there is a high prevalence of profound fatigue, unrefreshing sleep, and post-exertional exacerbation of symptoms in these patients. There also is sufficient evidence that pediatric ME/CFS can follow acute infectious mononucleosis and EBV" (p 201).

Recognition that research funding has been inadequate﻿"Remarkably little research funding has been made available to study the etiology, pathophysiology, and effective treatment of this disease, especially given the number of people afflicted" (p 9).

The Bad: Non-Specific Definition

The IOM report sends mixed messages to medical professionals. On the one hand, it states that ME/CFS is a "serious, complex" disease. But on the other, it presents diagnostic criteria that are oversimplified, giving the impression that this is not a serious, much less potentially fatal, illness. Of the two messages, the second will have the greater weight. Regardless of the encouraging language used in the report, medical professionals are much more likely to read a short definition than a 282-page document.

The new IOM definition is a highly reduced version of the Canadian Consensus Criteria, consisting of three non-specific (i.e. common to many illnesses) required symptoms, and two non-specific optional symptoms. Because it consists of non-specific symptoms, the IOM definition will capture a number of illnesses in addition to ME/CFS, making it useless for research and too broad for diagnosis. (This is precisely the problem with the Fukuda definition.)

(Contrary to popular belief, PEM is not unique to ME. Patients with early MS, B12 deficiencies, Hashimoto's disease, and lupus all experience a worsening of symptoms after exertion. Regardless of the severity and permutations of PEM, physicians will not see the fine points. Nor will they ever consider a worsening of symptoms after emotional or cognitive stress to be anything other than psychosomatic.)

IOM DefinitionDiagnosis of ME/CFS requires that a patient have the following three core symptoms:

A substantial reduction or impairment in the ability to engage in pre-illness levels of activities that persists for more than six months and is accompanied by fatigue - which is often profound - of new or definite onset, not the result of ongoing excessive exertion and not substantially alleviated by rest

The worsening of patients’ symptoms after any type of exertion - such as physical, cognitive, or emotional stress - known as post-exertional malaise

Unrefreshing sleep

At least one of the two following manifestations is also required:

Cognitive impairment

The inability to remain upright with symptoms that improve when lying down - known as orthostatic intolerance

Fatigue

The first symptom is still six months of fatigue. The IOM report states, "This 6-month requirement is supported by Nisenbaum and colleagues (1998), who showed that unexplained fatigue lasting for more than 6 months was related to symptoms included in the ME/CFS case definitions and that most other causes of similar fatigue do not last beyond 6 months." This implies that most cases of "similar fatigue" are self-resolving. In fact, the Nisenbaum study did not find that similar fatigue from other causes resolved within six months, because other causes of fatigue were not explored. The only conclusion Nisenbaum et al. reached was that six months the symptoms of CFS appeared to be a "threshold" for severity of symptoms. But their data indicated that this threshold was relatively modest, with percentages varying only slightly between the 1-5 month range and the 6-month or longer range.

Nevertheless, 6 months of "fatigue" is still required, which will miss all the sudden onset cases. This is problematic, because the initial "acute" phase of the disease is what is most puzzling to physicians. Patients who come to their doctors horribly ill several weeks after a "flu" are taken seriously, because the acute phase is quite dramatic. This is the phase in which test results (including ECGs and CBCs) are often abnormal, and in which physicians write prescriptions for numerous medications, none of which help and many of which harm patients. A case definition for a disease that can develop with such speed and severity should include a provision for sudden onset.

Six months of fatigue is still the predominant symptom in this definition, and because there are so few others, physicians will retain "chronic fatigue" as the go-to symptom for diagnosis. And because chronicity is established after six months, it is likely that physicians will dismiss patients with long-term fatigue in the absence of measurable signs, or combined with non-specific symptoms, as having psychological disorders.

PEM

The second symptom, PEM, will inevitably be interpreted as "exercise intolerance" by physicians. Exercise intolerance is a term that physicians understand, as it is commonly used in association with cardiopulmonary illnesses. Physicians may also interpret PEM as "avoidance of exercise," which, when combined with fatigue, sleep disorder, and cognitive problems (the result of lack of sleep) will lead them to think that a patient presenting these symptoms needs therapy or antidepressants.

PEM is non-specific. Contrary to popular belief, PEM is not unique to ME. Patients with early MS, B12 deficiencies, Hashimoto's disease, and lupus all experience a worsening of symptoms after exertion. Regardless of the severity and permutations of PEM, physicians will not investigate the fine points. Nor will they everconsider a worsening of symptoms after emotional or cognitive stress to be anything other than psychosomatic.

Doctors are taught in medical school to look for horses, not zebras, "horses" being common ailments, and "zebras" the more exotic or rare illnesses. In 2008, Drs. Philip R. Fischer, Jonathan N. Johnson, and Chad K. Brands wrote an an excellent article titled, "Fatigue, Exercise Intolerance, and Weakness: Lessons on Herding Zebras" in which they presented case studies demonstrating why physicians need to look beyond the obvious diagnosis. Of three pediatric cases in which the patients presented with typical symptoms of CFS, one had POTS, one had pheochromocytoma (benign adrenal tumor), and one had undiagnosed dermatomyositis (an inflammatory disease). All of these patients would meet the criteria for SEID.

Unrefreshing Sleep

Waking up tired, even after what may be considered adequate sleep, is universal in ME/CFS. It is also common in hypothyroidism, low adrenal function, fibromyalgia, narcolepsy, Lyme disease, allergies, sleep apnea and depression. Most doctors seeing a patient with the triumvirate of fatigue, unrefreshing sleep, and cognitive problems will conclude that the patient has depression, especially if standard blood tests are negative. The addition of "exertion intolerance" does not exclude depression, or distinguish ME/CFS from any number of illnesses in which an exacerbation of symptoms after exertion is a feature.

Cognitive Impairment and OI

The IOM included cognitive impairment as an optional symptom, even though "Impairments in cognitive functioning are one of the most frequently reported symptoms of ME/CFS" (p 96). Why cognitive impairment is optional is not clear, as it is one of the cardinal symptoms of ME/CFS.

Orthostatic intolerance was also included as an optional symptom, which is also puzzling. OI is usually included under autonomic dysregulation, which can also include other symptoms, such as migraine, temperature and blood pressure fluctuations, and other manifestations of autonomic dysfunction, all of which are found in patients with ME/CFS. There is also a tremendous overlap in symptoms between POTS (postural orthostatic tachycardia syndrome - the most common form of dysautonomia), and ME/CFS. (Anyone with POTS will fit the IOM definition of SEID, and vice versa,)Although the committee did not examine etiology, they would have greatly benefited from reading Dr. Jay Goldstein's book, The Limbic Hypothesis, in which he theorizes (with substantial evidence) that damage to the limbic system causes the symptoms of ME/CFS. The hypothalamus, which controls the autonomic nervous system, is located in the limbic system. It is a tiny organ, easily damaged by high fevers, hypoxia, and neurotoxins, It would have benefited the IOM if they had understood some of the major theories behind the symptoms that they chose to include in their definition, even if it was not part of their charge. As the experts predicted, the IOM lacked "the needed expertise to develop “clinical diagnostic criteria” for ME/CFS."Pain

The IOM stated that "Pain is a defining characteristic of ME/CFS ... The majority of ME/CFS patients experience some type of pain" (p 141). However, it rejected pain as a core symptom because because of the "less prominent role of myalgia in these patients relative to more core symptoms" (p 11). In making this statement, the IOM is overlooking their own research review. According to the studies the IOM reviewed, pain appeared with equal frequency to core symptoms.

The ultimate reason for rejecting pain was "while pain worsens ME/CFS when present, there is no conclusive evidence that the pain experienced by ME/CFS patients can be distinguished from that experienced by healthy people or those with other illnesses. Further, pain may be experienced in many areas, and while comprehensively assessing a patient’s pain symptoms is a challenging task, it is not specific to ME/CFS" (p 147).

Rejecting pain because it is non-specific ignores the fact that fatigue, exertion intolerance, sleep disorder, and the two optional symptoms are also not specific to ME/CFS. It also exhibits a failure to understand the basic physiology of pain. All pain is processed via the same neurological pathways, regardless of whether it is experienced by healthy people, or by people who are ill. Pain is a universal, and completely subjective, indicator that something is wrong in the body. The fact that so many people with ME/CFS experience pain cannot, and should not, be overlooked. To those who cannot escape it, pain is their most devastating symptom. Dismissing it as a significant feature of the illness basically relegates pain to "it's all in your head" (which, ironically, it is).

Exclusionary diagnoses not ruled out

Another major problem with the new criteria is that exclusionary diagnoses are no longer ruled out. Dr. Clayton was correct when she stated that there is nothing that says you can't get two conditions at the same time. You can have ME and hypothyroidism, or ME and cancer. Although Dr. Clayton was right in her assertion, a problem arises when you combine a lack of exclusionary diagnoses with a definition that requires only four non-specific symptoms. When patients present with these four symptoms, one of which is common to all diseases (fatigue), and there is no requirement that illnesses that match those symptoms (leukemia, Hashimoto's, Ehlers-Danlos, MS, lupus) be ruled out, there is the danger that patients who are "zebras" will be misdiagnosed.

There is also the strong probability that patients with major depression (MD) will be simultaneously diagnosed with SEID, which will be a roadblock for researchers as well as patients. Depression is a catchall for busy physicians who are presented with patients who primarily report fatigue and sleep disturbance. (And when their doctors ask, "Do you exercise regularly?" sleep-deprived patients usually say, "No, I am too tired.") As a number of studies have shown, patients with MD do not test the same as patients with ME/CFS. Because MD is not excluded from the diagnostic criteria, and because, like ME/CFS, there is no biomarker for depression, these patients will be included in studies. Some will then be shown to improve with exercise and therapy. (But not all. Because depression is a symptom of many underlying illnesses - hypothyroidism, autoimmune disease, cancer, diabetes - patients diagnosed with depression don't necessarily improve with exercise, therapy, or antidepressants.) Meanwhile, patients with ME will mistakenly be given antidepressants, which will only make them worse.

To prevent medical mismanagement of ME any diagnostic criteria must exclude major depression. And to secure appropriate treatment for diseases that are treatable, illnesses with similar symptoms must be ruled out.

Pediatric definition same as adult definition

It is a mistake to use the same definition for children and adults.

Pediatric ME is not the same as adult ME. Hypersomnia (sleeping round the clock) is more common in children than in adults. Symptoms present in equal severity (particularly stomach and headaches). Listlessness, ADD-like symptoms, double vision and other visual disturbances. and fever are also more common than in adults. Because their immune systems are ramped up, flu-like symptoms persist for much longer in children than in the adult population. All of these symptoms are easily observed by parents.

Six months of undiagnosed illness in a child can be devastating. It is also devastating to children when adults accuse them of "making up" their illness. The consequences of disbelief on the part of medical professionals and officials are that children are removed from their homes, placed in psychiatric institutions or foster care, where they are forced to suffer exercise and deprivation regimes that only make their illness worse. Any definition of ME for children needs to take these factors into account.

Bottom line

The IOM has described ME/CFS as a "serious, chronic, complex, multisystem disease," therefore it cannot, by its own description, reduce that "serious, complex" disease to four or five symptoms. To do so is a great disservice to the patients whose lives have been, and will continue to be, ruined by doctors who do not understand the illness, in part due to vague definitions.

What the IOM Should Have Done

Rather than invent a new definition, the IOM should have operationalized the algorithm devised by Jason's group, which has been tested and can identify patients with ME/CFS with 90% accuracy. The algorithm can be easily used by physicians as an initial screening tool once treatable conditions have been ruled out.

The second step in the diagnostic process should be the Canadian Case Definition, which not only provides enough detail to assess the illness, but utilizes the DePaul Symptom Questionnaire (DSQ) for additional information on severity and frequency of symptoms.

Until such time as we have a generally accepted biomarker, researchers should employ the CCC. It has been used in research for years, and has a verifiable track record.

The Absolutely Hideous

If the IOM failed in its charge to define the illness, it crashed and burned where naming it is concerned. Systemic Exertion Intolerance Disease is a name that means nothing. It is inappropriate, not just for this illness, but for any illness, for the following reasons:

1) All diseases are systemic, therefore the inclusion of "systemic" is meaningless. (The immune system, the endocrine system, and the nervous system all share cell receptors. Anything that affects one will affect the other two.)

2) "Exertion intolerance" will inevitably be translated into the more familiar term "exercise intolerance," which is seen in a number of illnesses. "Exertion intolerance" will be interpreted as either deconditioning or an "aversion" to exercise by general medical practitioners.

In addition to being useless, "SEID" represents a complete lack of familiarity with how diseases are normally named. Illnesses can be named according to a variety of traditions:

Place where the illness was first identified: ex. Lyme Disease, Gulf War Illness

Person, or people, who first described the illness: ex. Guillain-Barre, Alzheimer's

Major organs or systems affected: ex. kidney disease, heart disease

Primary mechanism or process: ex. muscular dystrophy

Famous person with illness: ex. Lou Gehrig's

Historical continuity: ex. Malaria (which means "bad air")

Illnesses are never named after a single non-specific symptom. If they were, we would have Coughing Disease, Diarrhea Disease, Itchy Skin Disease. Naming this illness after a non-specific symptom is what has caused so much damage over the past three decades. "SEID" repeats the error, reducing an illness that is complex, of unknown or varied etiology, and with no generally accepted biomarker, to a single non-specific symptom. "Exertion intolerance," in this context, is no better than "fatigue,"

(For those who are keeping track, this is the IOM's second fiasco in recent memory. The first was in 2012 when it re-named Gulf War Illness - another complex illness without an accepted biomarker - as "chronic multisymptom illness." Objections raised to that name ultimately culminated in a retraction.)

What the IOM Should Have Done

There were two viable options open to the IOM for naming this disease.

1) Keep the historical name myalgic encephalomyelitis. This would have lent continuity to both research and diagnosis. And, in spite of all protestations to the contrary, the name is accurate. The IOM itself stated that pain is "a defining characteristic of ME/CFS" (p 141). There is also clear evidence of CNS damage.

2) Call it Ramsay's Disease. This would have honored the first person to extensively describe, and treat, the illness, Dr. Melvin Ramsay, as well as putting to rest to all the arguments about whether there is or is not inflammation in the brain.

Other options (such as picking a few prominent symptoms out of the pile. e.g. "systemic-fatigue-sleep-disorder-exercise-intolerance-cognitive-impairment-disease") are not practical or medically accurate and should not be considered.

In sum: Be careful what you wish for

For decades patients and ME/CFS specialists have complained about the derogatory name "chronic fatigue syndrome." The discussion of what to call this disease has raged since the term CFS was first coined in the 1980s, leading many people to assume that no matter what you called this illness it had to be preferable to CFS. "Get rid of CFS," they said. "Anything is better."

Now we have a new name, and it is no better - possibly even a little worse - than CFS.

For years, physicians and researchers have said that the Fukuda definition is too broad, and captures patients with other illnesses. They devised a new definition, which they used for 10 years. But, it was "too long." Now we have a new definition that is even more non-specific than the Fukuda definition, and, because the IOM does not rule out illnesses with overlapping symptoms, it will capture even more people without ME, making it useless for both diagnosis and research.

The IOM has lived up to the phrase "A camel is a horse designed by a committee." In the attempt to reach a consensus among bureaucrats, stakeholders and physicians, it has designed an ungainly beast.

To quote Jim Binns, chair of the Research Advisory Committee on Gulf War Veterans' Illnesses, "The conclusions of the report show that it was a waste of money, The committee never had the expertise or the process to do a case definition."

On January 9, 2014, Attorney Jeannette Burmeister filed a federal lawsuit against HHS and NIH in the U.S. District Court for the Northern District of California for failure to comply with the requirements of the Freedom of Information Act (FOIA) regarding documents she requested relating to the Institute of Medicine (IOM) study of diagnostic criteria for ME/CFS. On September 2, the Court ordered the government to comply with Attorney Burmeister’s request. (You can read the full complaint here.)

The court's decision is a landmark in ME/CFS advocacy. Past efforts to obtain documents through FOIA have been problematic. In 2012, Craig Maupin completed a year-long investigation into FOIA compliance with CFS programs within the NIH. His requests were denied numerous times on the basis that records were "not found." However,

"In each case, the request was able to pinpoint the location of the files. Second, after responding to a request that "files could not be found", several appeals seemed to fall back on the "too broad" defense. Inconsistency between initial denials and appeals could raise speculation as to whether required records are missing, lost, destroyed, or simply not applied to FOIA, particularly, as an earlier request was denied on the basis that the records were not available." (CFS Report)Maupin gave the ORWH, the department currently responsible for ME/CFS, a D- for their lack of compliance with FOIA regulations.

Kudos to Jeannette Burmeister for succeeding where so many have encountered nothing but official obstruction and denial.______________________________

Reprinted with the kind permission of Jeannette Burmeister.

US District Court: HHS/NIH Violated Federal Law in Response to FOIA Request for IOM Documents

I am pleased to give an update on my FOIA lawsuit:

Yesterday, the United States District Court for the Northern District of California ruled that HHS and NIH (government) violated the Freedom of Information Act (FOIA) when they improperly withheld documents from me in response to my FOIA request regarding HHS’s contract with the Institute of Medicine (IOM) for the study of diagnostic criteria for ME/CFS.

Accordingly, the Court granted my motion for summary judgment and ordered the government “to produce, within 60 days, all documents responsive to [my] request that are not covered by any exemption to FOIA’s disclosure requirements.” [emphasis added] The Court also denied the government’s motion for summary judgment asking for a dismissal of my lawsuit.

I believe that holding HHS and NIH legally responsible for their violation of federal law is a tremendous victory for our patient population. However, since this litigation is ongoing, I will not, at this time, be able to comment further or answer any questions beyond the following details and quotes from the Court’s ruling. Although there will hopefully be more good news before the case is over.

In January of this year, I sued the government under FOIA for failure to respond to my FOIA request for documents regarding the HHS-IOM contract. I have been represented in this legal action by the global law firm of Baker & McKenzie LLP. Only after my filing of the lawsuit (and after the statutory time period for their response had lapsed) did the government produce a meager amount of documents despite the fact that my FOIA request was very broad.

It was apparent that the government’s search for responsive documents was woefully inadequate, as obviously existing documents covered by my request that would have been easily available to the government and that a reasonable document search would have uncovered were not provided. The Court agreed and held that the search was the result of “obviously an unreasonably narrow interpretation of Burmeister’s request.” [emphasis added] The Court further states, “Indeed, [the HHS FOIA specialist] explains in her supplemental declaration that a broader search (the one the government should have conducted given the actual language of Burmeister’s request) ‘is a completely different type of search and presumably would have resulted in a much larger production.’” [emphasis added]The Court goes on to address the unreasonably narrow interpretation of my FOIA request by the government in more detail:“And [the HHS FOIA specialist] is correct about that. For example, without listing every document that could be responsive to Burmeister’s actual request, it is obvious that all records relating to the original effort by HHS to enter into a sole-source contract with the Institute of Medicine, and documents relating to the subsequent decision to change course and proceed with a task order in response to expressions of concern by members of the public about the manner in which HHS was proceeding, would be responsive. Such records exist, but the government did not provide them to Burmeister.“Because [the HHS FOIA specialist’s] supplemental declaration demonstrates that the government adopted an unreasonably narrow interpretation of Burmeister’s request, because [the HHS FOIA specialist] concedes she would have performed a much broader search had she interpreted the request correctly, and because that search would have uncovered additional records responsive to the request, the government has ‘improperly withheld agency records’ in violation of FOIA.” [emphasis added]The Court then addresses the government’s meritless claim that my lawsuit is moot due to the government’s production of some documents after the complaint was filed despite the fact that the document search was inadequate:“To avoid this conclusion, the government argues that Burmeister’s lawsuit should be dismissed as moot. Specifically, the government contends that even if Burmeister had the right to file her lawsuit because HHS failed to respond to her request within the time period required by FOIA, its subsequent production to Burmeister moots the lawsuit, even if the production was deficient. At the hearing on this motion, counsel for the government insisted that the case law compels this result – he argued that even if the production was deficient, the case law required that the lawsuit be dismissed as moot and that Burmeister be left to submit a response to the government’s production explaining how she believed it was deficient, so that the government would have a chance to remedy the deficiencies. However, the case law says exactly the opposite of what counsel for the government represented at the hearing,” namely, “To moot a FOIA claim, however, the agency’s production must give the plaintiff everything to which he is entitled. [emphasis added] Otherwise, there remains some ‘effective relief’ that can be provided the plaintiff, and the case is not moot.”According to the Court, the government’s argument that I did not exhaust my administrative remedies and, thus, my lawsuit should be dismissed also fails:“The government also contends Burmeister’s lawsuit should be dismissed for failure to exhaust her administrative remedies with respect to her claim that the agency’s search was inadequate. Specifically, the government argues that it responded to Burmeister’s request on January 7, two days before Burmeister sued, and that Burmeister should have objected to HHS about the adequacy of the response before filing the lawsuit. But the government’s response was not postmarked until January 8, and Burmeister credibly asserts she did not receive it until several days after she filed her complaint. Nor, in any event, was the government’s response a final or complete one – in other words, it was not a real response. The real response (which was, as discussed above, inadequate) came on February 3. Because the government failed to timely respond to Burmeister’s records request, and because Burmeister did not receive a final decision from the government until after she filed this lawsuit, her case is properly before the Court.” [emphasis added]The 60-day period the Court allowed for the government to produce all documents responsive to my request (and not exempt under FOIA from production) runs on November 3. Let’s hope that the Court’s ruling will be a wake-up call for the government and a reminder that it is not above the law.__________

Jeannette Burmeister is an Attorney at Law licensed to practice law in California and Germany. Before contracting ME in 2006, she was an attorney at Baker & McKenzie, LLP. (She was disabled at age 34.) Ms. Burmeister writes a blog, “Thoughts About ME,” in which she discusses topical issues concerning the ME/CFS community.

The Boston University School of Public Health study on Gulf War Illness (see below) is interesting for a couple of reasons, one of which is the proposed use of intranasal insulin to reduce neuroinflammation in veterans with GWI. Given the recent study confirming brain inflammation in patients with ME/CFS, and the substantial overlap in symptoms between the two illnesses, it doesn't require a leap of the imagination to put two and two together. If intranasal insulin helps vets with GWI, it may very well help people with ME/CFS.

Another interesting point this study raises is the absolute disjuncture between scientific research and the IOM's position on GWI. In the IOM's 2013 report on GWI, it stated that "Specific etiological agents are unknown...There is a growing belief that no specific causal factor or agent will be identified."

Studies linking GWI to pyridostigmine have been in circulation since the 1990s (Abou-Donia MB, Lotti M and Moretto A.). A 1999 article, "Nerve Gas Antidote a Possible Cause of Gulf War Illness" (Charatan), cited a 385-page report written by Dr Beatrice Golomb, professor of medicine at the University of California and physician at the Veterans Affairs Medical Center, San Diego which concluded that "pyridostigmine bromide cannot be ruled out as a possible contributor to the development of unexplained or undiagnosed illness in some Gulf war veterans." (Update published in 2008) This report was submitted to the IOM, which rejected pyridostigmine bromide as a cause of GWI, as it had done previously. ("The epidemiologic data do not provide evidence of a link between PB and chronic illness in Gulf War veterans." IOM report, Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines ( 2000 ), page 252)

Fourteen years later, the IOM continued to deny a connection between pyridostigmine and GWI. It also denied a connection between the Gulf War and GWI, renaming it "chronic multi-symptom illness." If nothing else, the IOM has been consistent in its ability to whitewash reality.

If the IOM was able to ignore a 385-page report sponsored by the Rand Corporation, two decades of published research, and the testimony of Gulf War vets (to whom the IOM expressed appreciation for their "willingness ... to share their experiences and thoughts") they will certainly be able to turn a blind eye to two decades of research on ME/CFS. Like the Gulf War vets, they will freely acknowledge our suffering, but will ultimately turn a deaf ear to the "experiences and thoughts" of ME/CFS patients and those who care for them.

The question I have is this: Is having the IOM appear to "listen" worth the inevitable outcome? At what point do we stop accepting validation of our feelings as a legitimate response to the critical problems of having no FDA-approved treatment, virtually no NIH funding, and a definition that will continue to relegate us to the no-man's land of waste basket diagnoses?____________________________

Progress has been made toward understanding the physiological mechanisms that underlie Gulf War illness and identifying possible treatments, according to a report released Monday by a Congressionally mandated panel directed by a BU School of Public Health researcher.

Treatment research has increased significantly since 2008, and “early results provide encouraging signs that the treatment goals identified in the 2010 Institute of Medicine report are achievable,” the Research Advisory Committee on Gulf War Veterans’ Illnesses (RAC) said in a report presented to VA Secretary Eric Shinseki by the Committee’s scientific director, Roberta “Bobbie” White, chair of environmental health at BUSPH.

The Institute, part of the National Academies of Sciences, had forecast that “treatments, cures, and hopefully preventions” could likely be found with the right research.

The RAC report updates scientific research published since the Committee’s landmark report in 2008, which established that Gulf War illness was a real condition, affecting as many as 250,000 veterans of the 1990-91 Gulf War. The RAC Committee is composed of scientific experts and veterans.

“The conclusions of the 2008 RAC report had a substantial impact on scientific and clinical thinking about Gulf War illness, as well as the public acceptance of this disorder,” said White. The earlier report documented a number of studies that found evidence linking the illness to exposure to pesticides and pyridostigmine bromide (found in anti-nerve gas pills given to troops), as well as other toxic sources.

“Studies published since 2008 continue to support the conclusion that Gulf War illness is causally related to chemical exposures in the combat theater,” White said of the new report. “And many studies of the brain and central nervous system, using imaging, EEG and other objective measures of brain structure and function, add to the existing evidence that central nervous system dysfunction is a critical element in the disorder. Evidence also continues to point to immunological effects of Gulf War illness.”

Exposure to the nerve gas agents sarin and cyclosarin has been linked in several studies to changes in magnetic resonance imaging (MRI) that are associated with cognitive impairments — further supporting the nervous-system effects of those agents cited in the 2008 report.

“The Committee concludes that the evidence to date continues to point to alterations in central and autonomic nervous system, neuroendocrine, and immune system functions,” the report says.

Studies also continue to show that Gulf War illness is not associated with psychological stressors during the war, the panel said. Rates of PTSD and other psychiatric illnesses in Gulf War veterans are far below the rate of these disorders in veterans of other recent wars, and far below the rate of Gulf War illness.

In addition, the Committee said, new evidence has emerged suggesting that certain exposures may be linked to brain cancer in Gulf War veterans. Studies show that veterans who were most exposed to the release of nerve gas during the destruction of the Khamisiyah arms depot in Iraq have significantly elevated rates of death due to brain cancer.

Veterans who were exposed to the highest level of contaminants from oil well fires also have increased rates of brain cancer deaths, the report says.

The Committee encouraged studies exposing animals to toxic agents involved in Gulf War illness “because they can help to determine treatment targets in subgroups of veterans with specific exposures, for which there are known mechanistic pathways that cause illness and symptoms.”

In addition, “results from this work can be useful in protecting the health of future military personnel who will experience these exposures, as well as non-military populations with occupational or environmental exposures.”

The panel cited a number of “promising” treatment studies, including those testing certain dietary supplements, intranasal insulin, and continuous positive airway pressure to ease fatigue and pain and improve cognitive function.

A consortium of institutions led by BUSPH is studying markers in the blood and brain fluid, in addition to brain imaging (MRI and PET scans) and memory testing, to try to identify biomarkers of the condition. Studies also are planned on animals, to test initial treatments.

In a separate trial, BUSPH researcher Kim Sullivan and her colleagues are developing a possible treatment involving intranasal insulin, to target neuroinflammation. Researchers from the Boston VA Medical Center, the James J. Peters VA Medical Center in the Bronx, and the Icahn School of Medicine at Mount Sinai are involved in that trial, funded by a $1.7 million award from the Department of Defense.While the RAC panel applauded an increase in the number of treatment studies funded by the Department of Defense’s Congressionally Directed Medical Research Program, it expressed grave concerns about a lack of research on other health problems and mortality among Gulf War veterans.

“Very little research” has been conducted to determine rates at which veterans have been affected by neurological diseases such as multiple sclerosis or Parkinson’s disease, cancers, and reproductive problems, the panel said.

“No comprehensive information has been published on the mortality experience of U.S. Gulf War era veterans after the year 2000,” according to the report.

Gulf War illness refers to the chronic symptoms that affect veterans of that conflict at markedly elevated rates, compared to other veterans’ groups and to the U.S. population as a whole. Symptoms can vary from person to person, but typically include some combination of widespread pain, headache, persistent problems with memory and thinking, fatigue, breathing problems, stomach and intestinal symptoms, and skin abnormalities.

After reading the AHRQ study protocol, I was left with the distinct impression that the conclusions had already been reached, and the "systematic review" had simply been adjusted to fit them.

One question in particular had the undeniable scent of prior judgment:

"What harms are associated with diagnosing ME/CFS?"

This question undoubtedly refers to the CDC's refusal to include the 2-day CPET as part of their multi-site study. Beth Unger's justification for the exclusion was that the "physical toll would be too high" for patients.

But by the same token, the review is designed to include the PACE trial. What kind of verbal gymnastics will the P2P perform in order to conclude that the 2-day CPET is harmful while simultaneously recommending GET?

Jennie Spotila has done an in-depth analysis of the review (below) which clarifies what is wrong with the review, and spells out the consequences.

It’s a recipe for disaster on its own, and within the broader context of the NIH P2P Workshop it’s even worse. Let me show you some of the reasons why.

Remind Me What This Is

The systematic evidence review is the cornerstone of the P2P process. The P2P meeting on ME/CFS will feature a panel of non-ME/CFS experts who will produce a set of recommendations on diagnosis, treatment, and research.

Because the P2P Panel members are not ME/CFS experts, they need background information to do their job. This systematic evidence review done by the Oregon Health & Science University under contract to AHRQ will be that background information. The systematic evidence report will be presented to the Panel in advance of the public P2P meeting, and will be used to establish the structure of the meeting as well.

The systematic review is the foundation. If done correctly, it would be a strong basis for a meaningful workshop. If done poorly, then everything that follows – the workshop and the resulting recommendations – will crumble. Based on the protocol published yesterday, I think “crumble” is putting it mildly.

The Key Questions"You can’t get the right answer if you don’t ask the right questions." ~Dr. Beth Collins-Sharp, CFSAC Minutes, May 23, 2013, p. 12

As I wrote in January, the original draft questions for the evidence review included whether CFS and ME were separate diseases. That question is GONE, my friends. Now the review is only looking at two things:

What methods are available to clinicians to diagnose ME/CFS and how do the use of these methods vary by patient subgroups?

What are the benefits and harms of therapeutic interventions for patients with ME/CFS and how do they vary by patient subgroups?

These questions are based upon a single and critical assumption: ME and CFS are the same disease. Differences among patient groups represent subtypes, not separate diseases. The first and most important question is whether the ME and CFS case definitions all describe one disease. But they’re not asking that question; they have already decided the answer is yes.

The study protocol and other communications from HHS (including today’s CFSAC listserv message) state that the P2P Working Group refined these study questions. The implication is that since ME/CFS experts and one patient served on the Working Group, we should be satisfied that these questions were appropriately refined. But what I’m piecing together from various sources indicates that the Working Group did not sign off on these questions as stated in the protocol.

Regardless of who drafted these questions, they cannot lead to the right answers because they are not the right questions. And when you examine the protocol of how the evidence review will be conducted, these questions get even worse.Protocol Problems

The real danger signals come from the description of how this evidence review will be done. The issue is what research will be included and assessed in the review. For example, when asking about diagnostic methods, what definitions will be considered?

This evidence review will include studies using “Fukada [sic], Canadian, International, and others“, and the Oxford definition is listed in the table of definitions on page 2 of the protocol. That’s right, the Oxford definition. Oxford requires only one thing for a CFS diagnosis: six months of fatigue. So studies done on people with long-lasting fatigue are potentially eligible for inclusion in this review.

The description of the population to be covered in the review makes that abundantly clear. For the key question on diagnostic methods, the study population will be: “Symptomatic adults (aged 18 years or older) with fatigue.” There’s not even a time limit there. Three months fatigue? Four? Six? Presence of other symptoms? Nope, fatigue is enough.

There is a specific exclusion: “Patients with other underlying diagnosis,” but which conditions are exclusionary is not specified. So will they exclude studies of patients with depression? Because the Oxford definition does not exclude people with depression and anxiety. We’ve seen this language about excluding people with other underlying diagnosis before – and it results in lumping everyone with medically “unexplained” fatigue into one group. This protocol is set up to result in exactly that. It erases the lines between people with idiopathic chronic fatigue and people with ME, and it puts us all in the same bucket for analysis.

And what about the key question on treatment? What studies will be included there? All of them. CBT, GET, complementary/alternative medicine, and symptom-based medication management. It’s not even restricted to placebo trials; trials with no treatment, usual care, and head-to-head trials are all included.

Let’s do the math. Anyone with unexplained fatigue, diagnosed using Oxford or any other definition, and any form of treatment. This adds up to the PACE trial, and studies like that.

But it’s even worse. The review will look at studies published since January 1988 because that was the year “the first set of clinical criteria defining CFS were published.” (page 6) Again, let’s do the math: everything published on ME prior to 1988 will be excluded.

Finally, notice the stated focus of the review: “This report focuses on the clinical outcomes surrounding the attributes of fatigue, especially post-exertional malaise and persistent fatigue, and its impact on overall function and quality of life because these are unifying features of ME/CFS that impact patients.” (page 2) In other words, PEM = fatigue. And fatigue is a unifying concept in ME/CFS. Did anyone involved in drafting this protocol actually listen to anything we said at last year’s FDA meeting?

Bad Science

Maybe you’re thinking it’s better for this review to cast a broad net. Capture as much science as possible and then examine it to answer the key questions. But that’s not going to help us in this case.This review will include Oxford studies. It will take studies that only require patients to have fatigue and consider them as equivalent to studies that require PEM (or even just fatigue plus other symptoms). In other words, the review will include studies like PACE, and compare them to studies like the rituximab and antiviral trials, as if both patient cohorts were the same.

That assumption – that patients with fatigue are the same as patients with PEM and cognitive dysfunction – is where this whole thing falls apart. That assumption contaminates the entire evidence base of the study.

In fact, this review protocol makes an assumption about how the Institute of Medicine study will answer the same question. It is possible (though not assured) that IOM will design diagnostic criteria for the disease characterized by PEM and cognitive dysfunction. But this evidence review is based on an entirely different patient population that includes people with just fatigue. The conclusions of this evidence review may or may not apply to the population defined by the IOM.

It’s ridiculous!

But it’s the end use that really scares me. Remember that this systematic evidence review report will be provided to that P2P Panel of non-ME/CFS experts. The Panel will not be familiar with the ME/CFS literature before they get this review. And the review will conflate all these definitions and patient populations together as if they are equivalent. I think it’s obvious what conclusion the P2P Panel is likely to draw from this report.

I would love to be wrong about this. I would love for someone to show me how this protocol will result in GOOD science, and how it will give the P2P Panel the right background and foundation for the recommendations they will draft. Please, scientists and policy makers who read this blog – can you show me how this protocol will produce good science? Because I am just not seeing it.

What Do We Do?

This protocol is bad news but it is by no means the last word. Plans are already in motion for how the advocacy community can respond. I will keep you posted as those plans are finalized.

Make no mistake, this evidence review and P2P process are worse than the IOM study. We must respond. We must insist on good science. We must insist that our disease be appropriately defined and studied.

Not everyone agrees that the best way to oppose the IOM contract is to send comments to the committee. But, if you are boycotting the IOM contract, you cannot succeed by simply refusing to participate. Boycotts only work when you let people know what you are boycotting and why.

MEAdvocacy.org has set up a very simple means of letting key players in government know that you are boycotting the IOM process. All you have to do is click to send a letter.

The letter will be sent to President Obama, the Senate Committee on Health, Education, Labor and Pensions, the US House Committee on Labor, Health and Human Services, Education, and Related Agencies, the House Subcommittee on Health, Employment, Labor, and Pensions, HHS, NIH and all those who are in charge of subdivisions within HHS.

For those who have decided not to send comments to the IOM, this is your opportunity to get your message across to the federal government.

If you have something to say - say it.

Silence = Death._____________________

From MEAdvocacy.org

Tell Congress and HHS, IOM Definition for ME/CFS Set Up to Fail

Tell the Senate and House Committees controlling the Department of Health and Human Services, and HHS officials, the IOM definition effort for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is set up to fail - just like the one they devised for Gulf War Illness.

If another poor name and definition are created, it will have devastating consequences for one million Americans, and 17 million worldwide, for another 30 years. This needs to stop now before more money is wasted and more lives are ruined. The already existing Canadian Consensus definition and the name Myalgic Encephalomyelitis are excellent and should be adopted now.

You may edit the letter to personalize it. After you send it, please share it widely on message boards, social media and email.

The deadline for sending comments to the IOM for their upcoming public session is Tuesday, April 22. I encourage everyone to send comments. These become part of the public record - by law.

Why is this important?

The IOM contract and the P2P panel represent a turning point in our history. Thirty years ago, HHS tried to bury us with a silly name and a vague definition that made it impossible to conduct meaningful research. But, even after three decades of neglect - and outright dereliction of duty - we are still here.

There is no doubt in anybody's mind that HHS intends for the IOM not simply to bury us, but to drive so many nails in our coffins that we will never be able to rise up again. And yet, it was quite clear from the public meeting in January that the IOM is on the defensive.

Fifty of the world's leading experts in ME/CFS signed a letter to HHS, telling them that the IOM contract was a waste of time and money. And scores of patients and advocates have kept up a steady stream of pressure ever since.

They may have bigger guns, but we have more of them. And we have the U.S. Constitution.

The Bill of Rights

HHS would like us to sit down and shut up.

But I, for one, will never give up my First Amendment rights. They will have to pry my laptop from my cold, dead fingers before I give up my right to free speech.

This is not a good time to remain silent. If we say nothing, we are giving tacit acceptance of whatever the IOM decides to do. We can't dispute their decision afterwards if we say nothing now.

Public records are the only means of providing solid evidence that the ME/CFS community 1) opposes the IOM contract, and 2) wants the immediate adoption of the CCC and the name to be changed to ME.

The IOM is challenging us to a showdown. We should lock and load.

The following are one advocate's comments to the IOM. Feel free to use them as a template.

Send comments to this address before April 23: mecfsopensession@nas.edu

If you miss the deadline use this address: mecfs@nas.edu____________________________________

To: mecfsopensession@nas.edu

Dear Dr. Mundaca-Shah,

Please make my comment available in the Public Access File.

The IOM asked the ME/CFS patient community to weigh in on two questions:

1) In your opinion, what are the most important issues that healthcare providers should be educated about when it comes to diagnosis of ME/CFS?

a. Healthcare professionals must stop ignoring the seriousness of this illness, and stop psychologizing it.

b. Healthcare professionals must stop trying to get patients to exercise their way out of it. This is just making patients much sicker. Educate healthcare professionals about Post-Exertional "Malaise" (i.e. Post-Exertional Collapse). For instance, if a patient (diagnosed or not) tells a doctor that when they exercise they are incapacitated for days, that should set off alarm bells for healthcare professionals, and they must then educate the patient on how to (try to) avoid Post-Exertional "Malaise"/Collapse.

c. Healthcare professionals must use the Canadian Consensus Criteria for ME/CFS or the International Consensus Criteria for ME/CFS. They should not refer to the CDC's website or literature for ME/CFS, as it is inaccurate and the recommendations in it are hurtful to patients.

d. Healthcare professionals must be willing to do house calls for those who are too sick to leave their homes to get to a doctor's office. There are many of us in this situation, alone and without help or medical care.

2) What are your thoughts on the current terminology used to describe this disease:Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? If you could suggest new terminology, what would you suggest and why?

a. Firstly, the name "Chronic Fatigue Syndrome" is inaccurate, grossly demeaning and very inappropriate given the severity of the illness. It belittles the disease and the suffering of the patients. Many of us remain homebound or bedridden for decades.b. Secondly, the illness should be called what the World Health Organization calls it, M.E. -- myalgic encephalomyelitis. Recent research has found inflammation in the brains of patients with ME/CFS, which validates the name ME. This research must be acknowledged by the IOM.

c. Lastly, the name should not be further watered down and called "Multi-system" or "multi-symptom" anything.

The IOM has posted its agenda for the public meeting to be held on May 5, 2014. (You can view the agenda here.)If there is anybody who still believes that the IOM knows what it's doing, the list of speakers for that meeting should leave them scratching their heads.

The inclusion of Megan Arroll to speak about cognitive problems is not just baffling, it is mind-boggling. Megan works for the Optimum Health Clinic, which offers the following service to patients with ME/CFS:"The clinic offers a 3-month intervention which consists of a combination of neuro-linguistic programming (NLP), emotional freedom technique (EFT), life coaching and hypnotherapy/self-hypnosis constructed in a manner specific to the needs of those with ME/CFS. The primary aim of this approach is to reduce the anxiety that is associated with having a debilitating and unpredictable condition, improve emotional well-being and help individuals slowly manage and increase their activity within their own limits (ie, pacing)."It goes without saying that the clinic claims a significant success rate, as all such clinics do. In fact, Megan published a paper about the "improvement" in ME patients after participating in their program. (Read the paper here.) The basic premise behind OHS' approach, and indeed all "treatment programs" that utilize NLP, EFT, CBT, the Lightning Process, and so on, is that ME/CFS is caused by stress, therefore it can be treated by "life coaching." (Note: If stress caused ME/CFS, everyone on the planet would have it.)

I can't help but wonder, if the IOM committee were convened to review case definitions of Parkinson's disease, would they invite someone with training in neuro-linguistic programming? And why stop at NLP practitioners? There are some great stress reduction techniques out there. How about past-life regression? (I've heard past lives can wreak havoc on cognitive function.) Chakra balancing? Astral projection? If the IOM committee wants to consider every angle, the sky's the limit.

The inclusion of Akifumi Kishi is also puzzling. Akifumi Kishi is a Postdoctoral Fellow in the Division of Pulmonary, Critical Care and Sleep Medicine at the NYU School of Medicine. He has published two papers with Benjamin Natelson about sleep disturbance in people with ME/CFS and/or fibromyalgia. He is most certainly not an expert on ME/CFS, or on sleep disturbance in this patient group. The best Kishi can do is present the results of the two studies he published, neither of which was particularly well designed. (He did not so much as mention the alpha wave disruption in ME/CFS found by Moldofsky, an anomaly associated with all autoimmune diseases.)

Leonard Jason will be speaking on case definitions and diagnosis. They could not have chosen a better person to cover this topic. Nevertheless, the expression "casting pearls before swine" comes to mind. If the IOM committee can't tell the difference between the contributions of a psychologist who thinks ME/CFS is stress-induced and an epidemiologist with Jason's long experience, then how will the committee make a distinction between people who think "It's all in their heads" and researchers who know that numerous immune, neurological and metabolic abnormalities drive the disease?

The answer is that it won't. The whole idea behind the IOM committee and the P2P panel is that they will approach this complex disease tabula rasa - without an idea in their heads, which means giving equal weight to all theories, no matter how unfounded they may be.Nothing is more dangerous for patients with ME/CFS than people with blank slates for brains.

Let's write on those slates. Send an email to the IOM!

But can you boycott the IOM process and still send an email?

Of course! A boycott doesn't work if you don't let people know you are boycotting them. (Remember all those "Boycott Grapes" bumper stickers?)

Tell the committee that you do not support the IOM process. Tell them to adopt the CCC and tell them to change the name CFS to Myalgic Encephalomyelitis.

Author

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About me:I'm a 25-year veteran of CFIDS. I know what it is like to be bedbound for long stretches of time. I also know what it is like to recover, and to relapse. But this blog is not about my personal experience. It is intended to be a resource - a collection of anything that might be helpful to the CFIDS community: book reviews, advice, CFIDS news, research, advocacy, opinion, who's who in our community, fundraising... and occasionally a bit of humor.

Disclaimer: I am not a doctor, which means nothing I write, no matter how sensible it may be, should be interpreted as medical advice.